First-in-human dose escalation and expansion study of SYSA1801, an antibody-drug conjugate targeting claudin 18.2 in patients with resistant/refractory solid tumors.
Authors: Yakun Wang, Jifang Gong, Rongbo Lin, Shen Zhao, Jufeng Wang, Qianli Wang, Yanqiao Zhang, Dan Su, Jingdong Zhang, Qian Dong, Ling Lin, Wen Tian, Ying Chen, Yang Yang, Xueyuan Zhang, Xuechao Wan, Jinfeng Gao, Na An, Valerie Malyvanh Jansen, Lin Shen
Journal: Journal of Clinical Oncology (2023)

3016 Background: SYSA1801 is a MMAE antibody-drug conjugate (ADC) targeting claudin 18.2 (CLDN18.2), a tight junction protein broadly expressed in gastric, pancreatic, and other solid tumors. CLDN18.2 has a highly selective cell surface expression profile that is limited to normal gastric mucosa, making it a promising ADC therapeutic target. SYSA1801 has shown significant in vitro and in vivo anti-tumor activity in multiple cell lines and patient-derived xenografts expressing CLDN18.2. Methods: This is an open-label, multi-center, phase I study to evaluate the safety, tolerability, pharmacokinetics and efficacy of SYSA1801 in patients (pts) with histologically confirmed resistant/refractory solid tumors that express CLDN18.2 who progressed on or were intolerant to standard treatment, or had no standard treatment. This study consists of two parts; part 1 is a modified 3+3 dose-escalation design with five dose levels of SYSA1801 (0.5, 1, 2, 2.5 and 3 mg/kg) administered intravenously (IV) every 3 weeks (Q3W), followed by dose expansion at effective doses. Part 2 is a cohort expansion at the optimal dose. Here, we present the preliminary results of SYSA1801 for part 1. Results: As of Nov 5, 2022, 33 pts with a median age of 59 yrs (range 22-71) were enrolled to receive up to SYSA1801 3 mg/kg in part 1. 26 pts (78.8%) had gastric cancer (GC) and 7 pts (21.2%) had pancreatic cancer. ECOG PS was 0 in 5 pts (15.2%) and 1 in 28 pts (84.8%). 11 pts (33.3%) had been heavily pretreated (≥3 prior lines). Treatment-related adverse events (TRAEs) of any grade occurred in 25 pts (75.8%), in which 8 (24.2%) were ≥ grade 3. No treatment related death was reported. The most common TRAEs (occurring in &gt;20% of pts) were nausea (42.4%), vomiting (36.4%), dry eye syndrome (21.2%) and anemia (21.2%). Two DLTs (grade-3 nausea and vomiting) occurred at the 3 mg/kg dose. The optimal dose of SYSA1801 is being explored. Of 33 pts enrolled, 21 pts were evaluable for efficacy per RECIST v1.1. Objective response rate (ORR) was 38.1% (95% CI: 18.1-61.6%, 8 PRs) and disease control rate (DCR) was 57.1% (95% CI: 34.0-78.2%, 4 SDs). Among 17 evaluable pts with GC, ORR and DCR were 47.1% (95% CI: 23.0-72.2%, 8 PRs) and 64.7% (95% CI: 38.3-85.8%, 3 SDs). One pt with GC receiving SYSA1801 at 1 mg/kg IV Q3W tolerated treatment for 44 weeks with durable confirmed partial response ongoing at the time of analysis. Another pt with GC who failed previous anti-CLDN18.2 treatment achieved a confirmed PR on SYSA1801 2 mg/kg IV Q3W. Conclusions: SYSA1801 shows promising early signs of efficacy with a well-tolerated safety profile in pts with CLDN18.2-expressing resistant/refractory solid tumors, especially GC. Part 1 of the study is ongoing with part 2 to start when the optimized dose is determined in China; studies outside of Greater China including in the United States are being planned by Elevation Oncology. Clinical trial information: NCT05009966 .